Endothelin-1 Concentrations Research Articles

Endothelin-1 as a novel target for the prevention of metabolic dysfunction with intermittent hypoxia in male participants.

We examined the effect of intermittent hypoxia (IH, a hallmark feature of sleep apnea) on adipose tissue lipolysis and the role of endothelin-1 (ET-1) in this response. We hypothesized that IH can increase ET-1 secretion and plasma free fatty acid (FFA) concentrations. We further hypothesized that inhibition of ET-1 receptor activation with bosentan could prevent any IH-mediated increase in FFA. To test this hypothesis, 16 healthy male participants (32 ± 5 yr, 26 ± 2 kg/m2) were exposed to 30 min of IH in the absence (control) and presence of bosentan (62.5 mg oral twice daily for 3 days prior). Arterial blood samples for ET-1, epinephrine, and FFA concentrations, as well as abdominal subcutaneous adipose tissue biopsies (to assess transcription of cellular receptors/proteins involved in lipolysis), were collected. Additional proof-of-concept studies were conducted in vitro using primary differentiated human white preadipocytes (HWPs). We show that IH increased circulating ET-1, epinephrine, and FFA (P < 0.05). Bosentan treatment reduced plasma epinephrine concentrations and blunted IH-mediated increases in FFA (P < 0.01). In adipose tissue, bosentan had no effect on cellular receptors and proteins involved in lipolysis (P > 0.05). ET-1 treatment did not directly induce lipolysis in differentiated HWP. In conclusion, IH increases plasma ET-1 and FFA concentrations. Inhibition of ET-1 receptors with bosentan attenuates the FFA increase in response to IH. Based on a lack of a direct effect of ET-1 in HWP, we speculate the effect of bosentan on circulating FFA in vivo may be secondary to its ability to reduce sympathoadrenal tone.

Gender related differences in active renin, aldosterone and big endothelin concentration during head-up tilt testing in patients with isolated vasovagal syncope

Introduction and objectiveNeuroendocrine dysregulation seems to play the main role in liberation of abnormal vasovagal reflex, and the pathomechanism can be gender-related. The aim of the study was to assess changes in concentration of active renin (R), aldosterone (A) and big endothelin (BE) at rest and tilting in patients with vasovagal syncope in reference to gender and result of the head-up tilt test (HUTT).Material and methodsStudy involved 133 patients with syncope. In all HUTT were performed. Concentrations of the analyzed hormones were measured at the last minute of the rest, at the 10th minute of tilting and at the end of the test. An aldosterone/renin ratio (A/R) was calculated for each of the phases.ResultsHUTT(+) was observed in 87subjects (65%). During tilting a gradual increase of R and A was observed. The highest A/R was present in women HUTT(-) (p=0.040), contrary to non-fainting men in which decrease of A/R was accompanied with the highest absolute values at the end of the test (&gt;18.6 pg/ml and A/R ratio at the end of the test &lt;2.53 revealed to be independent predictors of syncope during tilt. The increase of R concentration during tilting &lt;1.26 fold and the lack of increase of A predicted syncope during passive phase. In men, A concentration at the end of the test &lt;44.0 pg/ml and the increase of A during tilting less than 2.10 fold, independently predicted positive result. None of analyzed parameters was pointed as an independent factor of syncope during passive phase. In women, R concentration at 10th minute of tilting &gt;18.6 pg/ml and A/R ratio at the end of the test &lt;2.53 revealed to be independent predictors of syncope during tilt. The increase of R concentration during tilting &lt;1.26 fold and the lack of increase of A predicted syncope during passive phase. In men, A concentration at the end of the test &lt;44.0 pg/ml and the increase of A during tilting less than 2.10 fold, independently predicted positive result. None of analyzed parameters was pointed as an independent factor of syncope during passive phase.ConclusionsThe activity of the vasoactive hormones is different in women and men and can determine the result of the test and the tolerance to passive tilting.

Biochemical and clinical evaluation of endothelial injury after distal or traditional transradial access in percutaneous interventions.

Distal transradial access (dTRA) has been proposed as an alternative to traditional transradial access (TRA) in cardiac catheterization. The study aimed to compare these two transradial approaches: TRA and dTRA in terms of clinical and biochemical aspects. Two hundred patients who qualified for the elective coronary procedure were included. The patients were assigned to one of the groups depending on their vascular access. The groups were compared in terms of perceived pain using the Visual Analogue Scale (VAS), time of gaining access, need for conversion, and local complications. Additionally, in forty patients circulating endothelial injury markers: endothelin 1 (ET-1), interleukin 8 (IL-8), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were assessed. Successful cannulation was obtained in 84 (100%) in the TRA group and in 98 (84%) subjects in the dTRA (P <0.001). dTRA was associated with higher level of pain perceived at the time of gaining vascular approach than TRA; median VAS score (interquartile range [IQR]): 4 (2-5) vs. 2 (2-4) (P = 0.04). The mean time (standard deviation [SD]) needed to cannulate the artery in dTRA was longer than in TRA: 81 (8) seconds vs. 50 (4) seconds (P = 0.04). ET-1 concentration was (SD) 2.08 (0.19) pg/ml [dTRA] vs. 2.00 (0.29) [TRA] pg/ml (P = 0.83); sVCAM-1: 12.71 (3.97) ng/ml vs. 12.86 (4.29) ng/ml (P = 0.98); IL-8: 8.81 (0.42) ng/ml vs. 9.15 (0.52) ng/ml (P = 0.62). Th number of complications after procedures did not differ between these two approaches. Cannulation of dTRA is associated with a lower success rate and higher pain perceived. dTRA is not inferior to TRA when safety issues and vascular injury are considered.

Influence of electroacupuncture on ghrelin and the phosphoinositide 3-kinase/protein kinase B/endothelial nitric oxide synthase signaling pathway in spontaneously hypertensive rats

ObjectiveTo investigate the influence of electroacupuncture (EA) on ghrelin and the phosphoinositide 3-kinase/protein kinase B/endothelial nitric oxide synthase (PI3K/Akt/eNOS) signaling pathway in spontaneously hypertensive rats (SHRs). MethodsEight Wistar-Kyoto rats were used as the healthy blood pressure (BP) control (normal group), and 32 SHRs were randomized into model group, EA group, EA plus ghrelin group (EA + G group), and EA plus PF04628935 group (a potent ghrelin receptor blocker; EA + P group) using a random number table. Rats in the normal group and model group did not receive treatment, but were immobilized for 20 min per day, 5 times a week, for 4 continuous weeks. SHRs in the EA group, EA + G group and EA + P group were immobilized and given EA treatment in 20 min sessions, 5 times per week, for 4 weeks. Additionally, 1 h before EA, SHRs in the EA + G group and EA + P group were intraperitoneally injected with ghrelin or PF04628935, respectively, for 4 weeks. The tail-cuff method was used to measure BP. After the 4-week intervention, the rats were sacrificed by cervical dislocation, and pathological morphology of the abdominal aorta was observed using hematoxylin-eosin (HE) staining. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of ghrelin, nitric oxide (NO), endothelin-1 (ET-1) and thromboxane A2 (TXA2) in the serum. Isolated thoracic aortic ring experiment was performed to evaluate vasorelaxation. Western blot was used to measure the expression of PI3K, Akt, phosphorylated Akt (p-Akt) and eNOS proteins in the abdominal aorta. Further, quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to measure the relative levels of mRNA expression for PI3K, Akt and eNOS in the abdominal aorta. ResultsEA significantly reduced the systolic BP (SBP) and diastolic BP (DBP) (P < 0.05). HE staining showed that EA improved the morphology of the vascular endothelium to some extent. Results of ELISA indicated that higher concentrations of ghrelin and NO, and lower concentrations of ET-1 and TXA2 were presented in the EA group (P < 0.05). The isolated thoracic aortic ring experiment demonstrated that the vasodilation capacity of the thoracic aorta increased in the EA group. Results of Western blot and qRT-PCR showed that EA increased the abundance of PI3K, p-Akt/Akt and eNOS proteins, as well as expression levels of PI3K, Akt and eNOS mRNAs (P < 0.05). In the EA + G group, SBP and DBP decreased (P < 0.05), ghrelin concentrations increased (P < 0.05), and the concentrations of ET-1 and TXA2 decreased (P < 0.05), relative to the EA group. In addition, the levels of PI3K and eNOS proteins, the p-Akt/Akt ratio, and the expression of PI3K, Akt and eNOS mRNAs increased significantly in the EA + G group (P < 0.05), while PF04628935 reversed these effects. ConclusionEA effectively reduced BP and protected the vascular endothelium, and these effects may be linked to promoting the release of ghrelin and activation of the PI3K/Akt/eNOS signaling pathway.

Involvement of ET-1/eNOS in the ameliorating effect of electroacupuncture on cardiac dysfunction in rats with spontaneously hypertensive

To observe the effect of electroacupuncture (EA) at "Neiguan" (PC 6) on cardiac function of ventriculus sinister in rats with spontaneously hypertensive (SHR), and to explore the mediation effect of endothelin-1 (ET-1)/endothelial nitric oxide synthase (eNOS). Six 12-week-old male Wistar Kyoto (WKY) rats were taken as the normal group. Eighteen 12-week-old SHR were randomly divided into a model group, an EA group and a sham EA group, 6 rats in each group. The rats in the EA group were treated with EA (disperse-dense wave, 2 Hz/15 Hz in frequency, 1 mA in current intensity) at "Neiguan" (PC 6), 30 min each time, once a day for 8 weeks. The rats in the sham EA group were treated with superficial needling at "Neiguan" (PC 6) with no electrical stimulation applied. After treatment, the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were tested by echocardiographic analysis. The left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), heart rate (HR), the maximum rate of increase/decrease of left ventricular pressure (±dp/dtmax) were detected. The serum content of ET-1 was detected by ELISA. Western blot was used to evaluate the expression of ETAR, eNOS in myocardial tissue of left ventricular. Compared with the normal group, LVEF, LVFS, +dp/dtmax/LVSP and -dp/dtmax/LVSP were decreased (P<0.01, P<0.05), while LVSP, LVEDP, +dp/dtmax and -dp/dtmax were increased (P<0.01) in the model group. Compared with the model group, LVEF, LVFS, +dp/dtmax/LVSP and -dp/dtmax/LVSP were increased (P<0.01, P<0.05), and LVSP and LVEDP were decreased (P<0.01) in the EA group. Compared with the normal group, the serum content of ET-1 and the expression of ETAR in myocardial tissue were increased (P<0.01), whereas expression of eNOS was decreased (P<0.01) in the model group. Compared with the model group, the serum content of ET-1 and the expression of ETAR in myocardial tissue were decreased (P<0.05), whereas expression of eNOS was increased (P<0.05) in the EA group. EA intervention may alleviate hypertensive cardiac function damage by up-regulating the expression of eNOS protein in myocardial tissue, down-regulating the serum content of ET-1 and the expression of ETAR protein in myocardial tissue.

Celastrol: A new potential therapeutic option in pulmonary hypertension associated to bronchopulmonary dysplasia

Bronchopulmonary dysplasia is a common pathology of premature newborns caused by oxidative stress and mechanical ventilation, resulting in hypoalveolization and impaired angiogenesis. It can be complicated by pulmonary hypertension (HTP-DBP) with excess mortality. Celastrol has anti-inflammatory and antioxidant properties. So, we addressed its potential therapeutic interest in HTP-DBP. Different concentrations of celastrol were used in a murine model of hyperoxic HTP-DBP (14 days with 90% O 2 ) and we evaluated hemodynamic parameters with echocardiography and lung remodeling with histological methods. Pulmonary arterial (PA) reactivity was addressed with myograph. Cytoplasmic calcium (Ca2 + i) response to endothelin-1 (ET-1) was evaluated in human fetal PA smooth muscle cells (fPASMC) with spectrophotometry in normoxic (21% O 2 ) and hyperoxic conditions (48 h with 60% O 2 ). Inflammation was addressed with IL6 ELISA assay in fPASMC. Celastrol reduces mortality at doses of 1 and 0.5 mg/kg/d compared to the hyperoxic control group. At 1 mg/kg/d, it normalizes PAAT (PA acceleration time) ( P < 0.001) and reduces vascular hyperreactivity to phenylephrine and ET-1 ( P < 0.001) with no effect on the alteration of the response to acetylcholine induced by hyperoxia. At doses of 0.1, 0.5 and 1 mg/kg/d, it decreases right heart hypertrophy and vascular remodeling (wall thickness) but has no effect on alveolization and vascular density (vWF staining). Finally, although celastrol (0.1 and 0.3 μM) decreases the increased Ca2 + i response to ET-1 in hyperoxia in fPASMC, expression of ET-1 receptors (Western blotting and qPCR for ET-A and ET-B) was unchanged. However, celastrol 0.5 μM decreases ET-1 concentration measured with an ELISA assay in human umbilical arterial endothelial cells. An increased concentration of IL6 was also observed in fPASMC in hyperoxia and was decreased by celastrol 0.5 μM. Celastrol has a preventive dose-dependent effect on some hallmarks of HTP induced by hyperoxia and could thus be considered as an interesting new potential therapeutic option for HTP-DBP.

Eosinopenia and increased markers of endothelial damage are characteristic of COVID-19 infection at time of hospital admission

In December 2019, a new virus has been discovered, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), leading to coronavirus disease 2019 (COVID-19). COVID-19 has been defined as an evolving disease with different phases. It starts with a mild or asymptomatic phase in which there is minimal disease. Thereafter, most patients recover, however, in 20% of the cases the infection worsens. It is hypothesized that eosinopenia, endothelial injury and the presence of smooth muscle autoantibodies are associated with the severity of the COVID-19. In a subset of 75 blood samples of patients with a SARS-CoV-2 infection at time of hospitalization and 30 healthy control samples concentrations of eosinophils, VEGF, VCAM, endothelin and smooth muscle autoantibodies were determined with hemocytometry, ELISA and immunofluorescence assays. In the group of patients with COVID-19 eosinophils (IQR = 0.0–0.01*109/L) were significantly decreased (p < .001), whereas markers of endothelial damage VCAM (IQR = 740–1120 ng/mL) and endothelin (IQR = 2.0–3.4 pg/mL) were significantly increased (p < .001) compared to the group of healthy controls (eosinophils IQR = 0.09–0.19*109/L, VCAM IQR = 362–561 ng/mL, endothelin IQR = 0.5–1.0 pg/mL). From the multivariate analysis, it is concluded that at time of hospitalization a combination of eosinopenia and increased markers of endothelial damage VCAM and endothelin are characteristic of COVID-19.

Effects of dietary non-starch polysaccharides level on the growth, intestinal flora and intestinal health of juvenile largemouth bass Micropterus salmoides

A 56-day feeding trial was conducted to evaluate the effects of dietary non-starch polysaccharide (NSPs) inclusion on the growth performance, intestinal flora and intestinal health of juvenile largemouth bass (6.00 ± 0.01 g) in quadruplicate. Seven isoproteic and isolipidic diets (crude protein 47.0%, crude lipid 12.5%) were formulated to contain 0%, 3%, 6%, 9%, 12%, 15% and 18% NSPs (each 100 g contains 32.26 g cellulose, 19.35 g arabinoxylan, 4.52 g β-glucan, 5.16 g mannan and 38.71 g pectin; named N0, N3, N6, N9, N12, N15 and N18), respectively. Weight gain rate, specific growth rate, protein efficiency ratio, protein and lipid deposition rate in the N12, N15 and N18 groups were significantly lower than in the N0 group. Plasma diamine oxidase activity and lipopolysaccharide and endothelin-1 concentration in the N15 and N18 groups were significantly higher than in the N0 group. Intestinal occludin, caludin-1, caludin-4, zonulaoccludens-1, interleukin-10, transforming growth factor-β, nuclear factor E2-related factor 2, B-cell lymphoma-2 (Bcl-2), B-cell lymphoma-xl and Bcl-2-associated athanogene expression levels and intestinal peroxidase, catalase and superoxide dismutase activities in the N15 and N18 groups were significantly lower than in the N0 group, while interleukin-8, interleukin-1β, tumor necrosis factor-α, kelch-like ECH-associated protein 1, caspase3, Bcl-2-assoxicated x protein and Bcl-2-associated death protein genes expression levels showed opposite trends. Moreover, the Shannon, Simpson, Chao and Ace indices and the abundance of Plesiomonas shigelloides, [Clostridium] dakarense and Romboutsia ilealis in the N18 group were significantly lower than in the N0 group, in contrast to the abundance of Paraclostridium bifermentans, Mycoplasma moatsii. Propionate, butyrate, valerate and total short-chain fatty acids (SCFA) contents in digesta of the N6 group were significantly higher than in the N0 group, while acetate, butyrate, valerate, caproate and total SCFA in digesta of the N18 group were significantly lower than in the N0 group. Results suggest that high NSPs diets increased intestinal permeability and abundance of pathogenic microorganisms, induced intestinal inflammation and intestinal epithelial cell apoptosis, but decreased intestinal flora α-diversity and SCFA contents, and ultimately impaired growth performance and intestinal health of juvenile largemouth bass. Conversely, low-dose NSPs inclusion had no negative effect on growth and improves intestinal health in juvenile largemouth bass, showing potential as prebiotics in aquafeed.

Endothelin-1 negatively correlates with functional capacity in patients with breast cancer receiving first line anthracycline-based chemotherapy

Abstract Funding Acknowledgements Type of funding sources: None. Background Endothelial dysfunction caused by anthracycline is one of the key mechanism of chemotherapy induced cardiomyopathy that ultimately resulted in heart remodeling and exercise limitations. An endothelial molecular factor Endothelin-1 (ET-1) is known to be extremely important in vasoconstriction and angiogenesis. Interestingly, ET-1 concentration is also altered in vascular injury following anthracycline administration suggesting a distinct association. Nonetheless, the correlation between ET-1 and functional capacity in chemotherapy induced cardiomyopathy remained largely unknown. Purpose To elucidate correlation between ET-1 serum concentration with left ventricular (LV) function and functional capacity using echocardiography and 6 minute walk test (6MWT) following anthracycline-based chemotherapy in patient with breast cancer. Methods This is a prospective study that involves 19 female participants diagnosed with breast cancer (stage IIA-IV) receiving first line chemotherapy with 4-8 cycles of anthracycline-based regiments. Baseline pre-chemotherapy characteristics, ET-1 serum concentration, echocardiography and 6MWT, followed by post-chemotherapy evaluation were measured. Additionally, 6MWT were also performed at 6 months and 12 months after completion of chemotherapy. Results ET-1 serum significantly increased post-chemotherapy (1.521±0.57 vs 1.817±0.52 pg/mL, p=0.0169) in comparison with baseline. 6MWT distance was decreased after initial pre-chemotherapy measurement (372.5±84.23), 366.8±51.96 and 358.5±51.97 post-chemotherapy and 6 months after chemotherapy completion respectively. Moreover, post-chemotherapy LV ejection fraction (LVEF) was significantly lower in high ET-1 group (≥ 1.817 pg/mL) as compared to patients with low ET-1 (70.39±3.75 vs 65.80±2.49, p=0.0465) regardless comparable baseline LVEF. In addition, Pearson’s correlation test displayed a tendency of negative correlation between post chemotherapy ET-1 with 6MWT distance post-chemotherapy and 6 months after chemotherapy completion (r = -0.264, p=0.2745, 95% CI = -0.64-0.22 and r = -0.172, p=0.4803, 95% CI = -0.58-0.3). Conclusion Collectively, these findings strongly suggest that ET-1 may serve as a novel biomarker to predict compromised functional capacity in cancer patients underwent chemotherapy, arguably requires further investigations.

Elevated aqueous endothelin-1 concentrations in advanced diabetic retinopathy.

Endothelin-1 (ET-1) is a potent vasoconstrictor which seems to be involved in the pathogenesis of diabetic retinopathy (DR). However, studies on intraocular ET-1 in DR have been limited. Thus, we investigated aqueous ET-1 levels in patients with DR. A total 85 subjects were included in this prospective study. Those were classified into three groups: advanced DR group included those with severe nonproliferative DR or proliferative DR, whereas early DR group included those with mild nonproliferative DR or moderative nonproliferative DR. Those who underwent cataract surgery and had no concomitant ocular disease were included in the control group. Aqueous humor levels of ET-1 were obtained before intravitreal bevacizumab injection (IVB) and after 1 month for the DR patients, and at the time of cataract surgery for the control group. Advanced DR group included 40 eyes (47.1%), whereas early DR group did 19 eyes (22.4%), and control group (26 eyes, 30.5%). Mean aqueous ET-1 level was 10.1±4.1 pg/mL (6.0-21.0 pg/mL) in advanced DR group, 1.9±0.7 pg/mL (0.6-2.8 pg/mL) in early DR group, and 2.1±1.0 pg/mL (0.7-3.9 pg/mL) in control group (P < 0.001). Advanced DR group was further subdivided into severe nonproliferative DR (15 eyes, 12.8%) and proliferative DR (25 eyes, 34.3%). Mean aqueous ET-1 level was 10.1±4.3 pg/mL (6.0-20.1 pg/mL) in patients with severe nonproliferative DR, and 10.0±4.0 pg/mL (6.0-21.0 pg/mL) in those with proliferative DR (P = 0.928) at baseline. Mean ET-1 level at 1 month after intravitreal injection was 2.5±1.0 pg/mL (0.3-4.8 pg/mL) in patients with severe proliferative DR and 2.9±1.7 pg/mL (1.0-7.0 pg/mL) in those with proliferative DR (P = 0.443). Mean aqueous ET-1 level was significantly reduced in both groups (P < 0.001, respectively). The mean aqueous ET-1 level was significantly higher in the eyes with advanced DR than those with early DR and the control group. The mean aqueous ET-1 level was significantly reduced after intravitreal injections in the advanced DR group. Based on our results, future studies on the exact role of ET-1 in the pathogenesis of DR and future implication for intervention would be helpful for managing DR.

Endothelin-1 response to whole-body vibration in obese and normal weight individuals.

Upregulation of endothelin‐1 (ET‐1) is the hallmark of various cardiovascular diseases (CVD). The purpose of the present study was to assess the ET‐1 response to an acute bout of whole‐body vibration (WBV) in humans and to determine the role of adiposity. Twenty‐two participants volunteered for the study; they were grouped into overweight/obese [(OW/OB): n = 11, Age: 33 ± 4 years, Body mass index (BMI): 35 ± 10 kg/m2] or normal weight [(NW): n = 11, Age: 28 ± 7 years, BMI: 21 ± 2 kg/m2]. Participants engaged in 10 cycles of WBV exercise (1 cycle = 1 min WBV followed by 30 s of rest). Blood samples were analyzed for ET‐1 pre‐WBV (PRE), immediately post (POST), 1 h (1H), 3 h (3H), and 24 h (24H) post‐WBV. There was a significant time main effect of WBV on circulating ET‐1 (F = 12.5, p < 0.001); however, the ET‐1 response was similar (F = 0.180, p = 0.677) between groups. Specifically, compared to PRE, a significant increase in ET‐1 was observed at 1H (p = 0.017) and 3H (p = 0.025). In addition, concentrations of ET‐1 were significantly lower at 24H compared to PRE (p = 0.019), 1H (p < 0.001), and 3H (p < 0.001). Maximal oxygen uptake during WBV was similar between the two groups. Acute WBV resulted in an initial rise in ET‐1, followed by a significantly lower ET‐1 at 24H in both groups. Findings support the utility of routine WBV exercise to elicit a decrease in ET‐1 and improve CVD risk, similar to what has been reported with traditional modes of exercise.

Changes in Inflammatory Markers in Patients with Chronic Thromboembolic Pulmonary Hypertension Treated with Balloon Pulmonary Angioplasty.

Background: Inflammatory response and endothelial dysfunction contribute to the progression of chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to assess changes in biomarkers involved in those processes in inoperable CTEPH patients treated with balloon pulmonary angioplasty (BPA). Methods: We enrolled 20 patients with inoperable CTEPH qualified for BPA and a control group. Interleukin 6, 8, 10 (IL-6, IL-8, IL-10), monocyte chemoattractant protein-1 (MCP-1), and C-reactive protein (hsCRP) constituted the markers of systemic inflammation. Endothelin 1 (ET-1) served as a marker of endothelial dysfunction. Selected markers were assessed before the BPA treatment, 24 h after the first BPA, and six months after completion of the BPA treatment. Results: At baseline, the CTEPH patients had increased serum concentrations of IL-6, IL-8 and ET-1. Twenty-four hours after a BPA session, we observed an increase in concentrations of IL-6 (∆ = 3.67 (1.41; 7.16); p < 0.001), of IL-10 (∆ = 0.25 (0; 0.47); p = 0.003), of MCP-1 (∆ = 111 (60.1; 202.8); p = 0.002), and of hsCRP (∆ = 4.81 (3.46; 8.47); p < 0.001). Six months after completion of the BPA treatment, there was a decrease in concentrations of IL-6 (∆ = −1.61 (−3.11; −0.20); p = 0.03), of IL8 (∆ = −3.24 (−7.72; 0.82); p = 0.01), and of ET-1 (∆ = −0.47 (−0.96; 0.05); p = 0.005). Conclusions: Patients with inoperable CTEPH exhibit increased systemic inflammation and endothelial dysfunction, which improves after completion of the BPA treatment. A single BPA session evokes an acute inflammatory response.

Fetal inflammatory response and endothelial dysfunction in newborns from mothers with exacerbation of cytomegalovirus infection during the second trimester of pregnancy

Aim. To study the fetal inflammatory response and endothelial dysfunction in newborns from mothers with an exacerbation of cytomegalovirus infection (CMVI) in the second trimester of pregnancy. Materials and methods. We examined 90 newborns with an antenatal history, uncomplicated and aggravated by the acute phase of chronic CMVI, diagnosed in their mothers at 21-24 weeks of gestation. The concentration of TNFα, IL-6, and endothelin-1 was determined in cord blood serum. The control group consisted of 30 newborns whose intrauterine development proceeded against the background of physiological pregnancy seronegative for cytomegalovirus (CMV). The main group included 60 newborns, which were divided into 2 subgroups. Subgroup 1 included 30 newborns from mothers who had an acute phase of chronic CMVI, leading to the development of chronic compensated placental insufficiency, subgroup 2 consisted of 30 newborns from mothers with exacerbation of CMVI, initiating the formation of chronic subcompensated placental insufficiency. Results. In the control group, DNA of CMV, IgM antibodies to CMV and IgG antibodies to CMV were not detected. In the main group, in newborns of subgroup 1, compared with the control, DNA of CMV, both in the cord blood and in the nasopharyngeal aspirate, was isolated in 3.3 % of cases, and was not detected in scrapings of the buccal epithelium. The titers of IgG antibodies to CMV were determined in the ratio of 1: 100 in 36.7 %, 1: 200 in 43.3 %, 1: 400 in 13.3% and 1: 800 in 6.7 % of cases. At the same time, in mother-newborn pairs, higher titers of IgG antibodies to CMV in pregnant women, compared with those in their offspring, were detected in 18 cases, and equal titers of IgG antibodies to CMV were detected in 12 dyads. In the control group, the concentration of TNFα was equal to (Me) 16.2 (12.9-32.7) pg/ml, IL-6 – 1.93 (1.65-2.21) pg/mL, endothelin-1 – 0.52 (0.45–1.21) fmol/mL. In subgroup 1 of the main group, in comparison with the control one, there was an increase in the concentration of TNFα by 2.6 times (p=0.000001), IL-6 – by 2.1 times (p = 0.000001) and endothelin-1 – by 2.1 time (p = 0.000002). In newborns of subgroup 2, compared with subgroup 1, CMV antigens were identified in the blood in 6.7 % (p &gt; 0.05), and in nasopharyngeal aspirate – in 10% (p&gt;0.05) in the absence of identification of the CMV genome in the buccal epithelium. In 6.7%, IgM antibodies to CMV were detected. IgG antibodies to CMV 1:800 were detected more often (in 33.3%, p&lt;0.05), as well as equal titers of IgG antibodies to CMV in 20 mother-offspring pairs (p&lt;0.05). There was an increase in the concentration of TNFα by 1.47 times (p=0.0076), IL-6 - by 1.33 (p = 0.0016) and endothelin-1 - by 1.5 times (p = 0.0161), respectively. Conclusion. In the offspring of mothers who had an exacerbation of CMVI in the second trimester of pregnancy and with the presence of chronic subcompensated placental insufficiency, compared with newborns from women with the acute phase of chronic CMVI at similar gestation periods and formed chronic compensated placental insufficiency, higher levels of pro-inflammatory cytokines and endothelin-1 are recorded, indicating activation of the fetal immune system as a result of viral aggression and penetration of IgG to CMV of maternal origin.

Histological and Physiological assessment of Endothelin-1 and Cholesterol in breast cancer of women

The current study included two aspects, one of which is histological and the other physiological. It included (75) blood samples from women with breast cancer, in addition to (15) blood samples for healthy women as control, in addition to collecting tissue biopsy from the mammary glands of some women whose blood samples were drawn Including them in advance. Those diagnosed with breast cancer and ages ranged between 38-68 years, where the study was conducted from 1 May 2019 to 2 October 2019. Gland tissue and the owner of those tumours swelling of the axillary lymph nodes. Another cancer that was found was papillary carcinoma, where epithelial hyperplasia appeared in the form of large papillae that filled the cavity of the gland. There is a large number of white blood cells and severe hematoma. Another type of gland cancer discovered is cribriform carcinoma, which is a rare case. Invasive cancer is the most dangerous, as it is observed in the glandular tissue with the presence of agglutination and crowding of tumour cells and tumour cysts. The study also showed haematological changes characterized by a highly significant concentration of Endothelin-1 (P&lt; 0.01) in the blood of women with breast cancer group 5 and group 4, compared to the control group as a usual case. At the same time, there was a significant increase (P &lt; 0.05) in the con- centration of Endothelin-1 in infected women in groups 3, 2 and 6 compared to the control group. The study showed a very significant decrease (P &lt; 0.01) in the cholesterol concentration of women with breast cancer of group 5, and group 6 compared to the control group, while its level decreased significantly (P ≤ 0.05) in-group 4 compared to the control group.

N-Carbamoylglutamate Supplementation on the Digestibility, Rumen Fermentation, Milk Quality, Antioxidant Parameters, and Metabolites of Jersey Cattle in High-Altitude Areas.

This study aimed to assess the impact of the dietary supplementation of N-carbamoylglutamate (NCG) on nutrient digestibility, rumen fermentation, milk quality, oxidative stress, and metabolites in the plasma and feces of Jersey cattle under high altitude with the hypoxic condition. A total of 14 healthy lactating Jersey dairy cows with similar body conditions were selected and randomly divided into 2 groups. The control group (CON group, N = 6 replicates) was fed with a conventional complete diet, whereas the experimental group (NCG group, N = 8 replicates) received 20 g/d per head NCG supplementation. The experiment lasted for 60 days, the adaptation period was 12 days, and the formal experiment period was 48 days. Except that the NCG group showed an upward trend in dry matter intake (DMI) (p = 0.09) and the fermentation parameters, the molar proportion of butyric acid tended to decrease (p = 0.08); the two groups had no significant differences (p > 0.05) in nutrients digestibility, plasma immunity, and antioxidant ability. However, compared with the CON group, the milk fat rate and blood oxygen saturation of the NCG group showed an upward trend (p = 0.09). For indexes associated with altitude stress, the contents of thyroxine, transferrin, and endothelin both decreased significantly (p < 0.05) in the NCG group. Meanwhile, heat shock protein (p = 0.07) and aldosterone (p = 0.06) also showed a downward trend. A total of 114 different metabolites were identified from feces and plasma, 42 metabolites were derived from plasma that mainly included 5 kinds of Super Class, and 72 metabolites were derived from feces that mainly included 9 kinds of Super Class. The significantly increased plasma differential metabolites were 2,5-dihydroxybenzoate and salicyluric acid, and the significantly increased fecal differential metabolites were Butenafine (fold change > 2). Pathway analysis showed that after applying NCG as a feed additive, the changes of the Jersey dairy cows mainly focused on amino acid metabolism and lipid metabolism. These results indicated that adding NCG to the diet can prevent the hypoxic stress state of lactating Jersey cows in high-altitude areas and has a tendency to improve milk quality.

Dual endothelin receptor antagonism increases resting energy expenditure in people with increased adiposity.

Increased adiposity is associated with dysregulation of the endothelin system, both of which increase the risk of cardiovascular disease (CVD). Preclinical data indicate that endothelin dysregulation also reduces resting energy expenditure (REE). The objective was to test the hypothesis that endothelin receptor antagonism will increase REE in people with obesity compared with healthy weight individuals. Using a double blind, placebo-controlled, crossover design, 32 participants [healthy weight (HW): n = 16, BMI: 21.3 ± 2.8 kg/m2, age: 26 ± 7 yr and overweight/obese (OB): n = 16, BMI: 33.5 ± 9.5 kg/m2, age: 31 ± 6 yr] were randomized to receive either 125 mg of bosentan (ETA/B antagonism) or placebo twice per day for 3 days. Breath-by-breath gas exchange data were collected and REE was assessed by indirect calorimetry. Venous blood samples were analyzed for concentrations of endothelin-1 (ET-1). Treatment with bosentan increased plasma ET-1 in both OB and HW groups. Within the OB group, the changes in absolute REE (PLA: -77.6 ± 127.6 vs. BOS: 72.2 ± 146.6 kcal/day; P = 0.046). The change in REE was not different following either treatment in the HW group. Overall, absolute plasma concentrations of ET-1 following treatment with bosentan were significantly associated with kcal/day of fat (r = 0.488, P = 0.005), percentage of fat utilization (r = 0.415, P = 0.020), and inversely associated with the percentage of carbohydrates (r = -0.419, P = 0.019), and respiratory exchange ratio (r = -0.407, P = 0.023). Taken together, these results suggest that modulation of the endothelin system may represent a novel therapeutic approach to increase both resting metabolism and caloric expenditure, and reduce CVD risk in people with increased adiposity.NEW & NOTEWORTHY Findings from our current translational investigation demonstrate that dual endothelin A/B receptor antagonism increases total REE in overweight/obese individuals. These results suggest that modulation of the endothelin system may represent a novel therapeutic target to increase both resting metabolism and caloric expenditure, enhance weight loss, and reduce CVD risk in seemingly healthy individuals with elevated adiposity.

Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS)

BackgroundFatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS.MethodsWe studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs). 14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS. Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs. In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers.ResultsFive of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding. A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs.ConclusionA subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups.

Effects of Physical Prehabilitation on the Dynamics of the Markers of Endothelial Function in Patients Undergoing Elective Coronary Bypass Surgery.

Our aim in this study was to evaluate the effect of physical training performed before CABG on the perioperative dynamics of the serum levels of asymmetric dimethylarginine (ADMA) and endothelin-1 (ET-1) of patients with stable coronary heart disease (CHD). Patients in the preoperative period were randomized into two groups: the training group (n = 43) underwent high-intensity treadmill training; the patients in the control group (n = 35) received no training before the procedure. The serum concentrations of ADMA and ET-1 were determined in the perioperative period, and the course of the early postoperative period was analyzed. In the training group, we found a significantly lower incidence of postoperative complications during hospital stays (p = 0.013). At the end of the training program, the ADMA levels were 1.8 times higher in the controls than in the training group (p = 0.001). We found that type 2 diabetes increased the probability of complications by 12 times (OR: 12.3; 95% CI: 1.24–121.5; p = 0.03), as well as elevating the concentration of ET-1 on the eve of surgery (OR: 10.7; 95% CI: 1.4–81.3; p = 0.02). Physical prehabilitation reduced the likelihood of complications nine times (OR: 0.11; 95% CI: 0.02–0.83; p = 0.03). The AUC was 0.851 ± 0.07 (95% CI: 0.71–0.98). The obtained results indicate the benefit of physical training during the prehabilitation stage since it can help to preserve endothelial function.

Increased Circulating Endothelin 1 Is Associated With Postoperative Hypoxemia in Infants With Single-Ventricle Heart Disease Undergoing Superior Cavopulmonary Anastomosis.

BackgroundInadequate pulmonary vascular growth results in morbidity for many children with single‐ventricle heart disease (SVHD). Endothelin 1 (ET1) is a potent vasoconstrictor and stimulator of pulmonary artery smooth muscle proliferation. Circulating ET1 levels and their association with outcomes have not been studied during early SVHD palliation. We aimed to define circulating levels of ET1 in patients with SVHD undergoing stage 2 palliation and evaluate their relationship to postoperative hypoxemia. We hypothesized that patients with SVHD with higher ET1 concentration would have a greater post–stage 2 hypoxemia.Methods and ResultsProspective cohort study of 55 subjects with SVHD undergoing stage 2 palliation and 50 controls. Samples for ET1 analysis were collected at preoperation (systemic and pulmonary vein) and 2, 24, and 48 hours postoperation for cases and a single time point for controls. The primary outcome was percentage of first 48 postoperative hours with clinically significant hypoxemia (saturation, <70%). ET1 concentration was lower in preoperative cases than controls (2.2 versus 2.7 pg/mL; P=0.0015) and in the pulmonary vein than systemic vein (1.7 versus 2.2 pg/mL; P<0.001). ET1 level increased by 2 hours postoperation and trended back to baseline by 48 hours. Higher preoperative pulmonary vein ET1 and 2 hours postoperative ET1 were associated with larger hypoxemia burden (10.6% versus 2.7% [P=0.0081]; and 7.6% versus 3.2% [P=0.01], respectively). Multivariable testing demonstrated ET1 concentration and cardiopulmonary bypass time were associated with hypoxemia, whereas catheterization measurements and clinical variables were not.ConclusionsInfants with SVHD with higher perioperative ET1 concentration experience more post–stage 2 hypoxemia. ET1 activity may be a modifiable risk factor of pulmonary vascular inadequacy for stage 2 palliation.

Active components of Descurainia sophia improve lung permeability in rats with allergic asthma by regulating airway inflammation and epithelial damage

The present study investigated the effect of active components of Descurainia sophia on allergic asthma and explored the underlying mechanism. SD male rats were randomly divided into a normal group(NC), a model group(M), a D. sophia decoction group(DS), a D. sophia fatty oil group(FO), a D. sophia flavonoid glycoside group(FG), a D. sophia oligosaccharide group(Oli), and a positive drug dexamethasone group(Y). The allergic asthma model was induced in rats by intraperitoneal injection of ovalbumin(OVA) and aluminum hydroxide gel adjuvant(sensitization) and atomization of OVA solution(excitation). After modeling, asthma-related indicators, tracheal phenol red excretion, inflammatory cell levels in the peripheral blood, lung permeability index(LPI), and oxygenation index(OI) of rats were detected. The pathological changes of lung tissues were observed by HE staining. Enzyme-linked immunosorbent assay(ELISA) was used to detect the content of inflammatory factors immunoglobulin E(IgE), interleukin-4(IL-4), and interferon-γ(IFN-γ) in the bronchoalveolar lavage fluid(BALF) and the content of endothelin-1(ET-1) and angiotensin-converting enzyme(ACE) in lung tissue homogenate. The serum content of nitric oxide(NO) was detected by colorimetry. Western blot was employed to determine the protein expression of Toll-like receptor 4(TLR4), nuclear factor κB-p65(NF-κB-p65), phosphorylated NF-κB-p65(p-NF-κB-p65), myosin light chain kinase(MLCK), vascular endothelial cadherin(VE cadherin), connexin 43, and claudin 5, and the mechanism of active components of D. sophia on allergic asthma was explored. As revealed by the results, the M group showed extensive infiltration of inflammatory cells around the bronchus of the lung tissues of the allergic asthma rats, thickened bronchial wall, severely deformed alveolar structure, increased number of wheezes, the content of IgE, IL-4, ET-1, and ACE, inflammatory cells, and LPI, and reduced latency of asthma, tracheal phenol red excretion, IFN-γ, NO content, and OI. After the intervention of the active components of D. sophia, the DS, FO, FG, Oli, and Y groups showed improved asthma-related indicators, tracheal phenol red excretion, and lung tissue lesions in allergic asthma rats, and the effects in the FO and Oli groups were superior. The content of inflammatory factors in BALF was recovered in the DS, FO, and Y groups and the FG and Oli groups. The number of inflammatory cells in rats was reduced in the DS and FO groups, and the FG, Oli, and Y groups to varying degrees, and the effect in the FO group was superior. DS, FO, Oli, and Y reduced ET-1, ACE, and LPI and increased NO and OI. FG recovered NO, ET-1, ACE, LPI, and OI to improve lung epithelial damage and permeability. Further investigation of inflammation-related TLR4/NF-κB pathways, MLCK, and related skeleton protein levels showed that TLR4, NF-κB-p65, p-NF-κB-p65, and MLCK levels were increased, and VE cadherin, connexin 43, and claudin 5 were reduced in the M group. DS, FO, FG, Oli, and Y could reduce the protein expression related to the TLR4 pathway to varying degrees, and regulate the protein expression of MLCK, VE cadherin, connexin 43, and claudin 5. It is inferred that the active components of D. sophia improve lung permeability in rats with allergic asthma presumedly by regulating the TLR4/NF-κB signaling pathway to improve airway inflammation, mediating MLCK and connexin, and regulating epithelial damage.